Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling.

Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and p-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.